Viral hepatitis is a group of severe diseases that do harm to human health, the causative agents of which are a group of different hepatovirus. There are 7 types of hepatitis virus found hitherto, which are HAV, HBV, HCV, HDV, HEV and possible TTV and HGV. Among them, Hepatitis C virus (HCV) is a causative agent that results in Hepatitis C. Though Hepatitis C was originally identified as non-A, non-B hepatitis acquired by transfusion, the subsequent research showed that Hepatitis C virus is propagated not only by transfusion, but also by other ways via alimentary tract, sex act and so on. At present there are approximately more than 100 million persons infected with HCV in the world, and approximately 50%-90% of those persons will develop chronic disease. 8-46% and 11-19% from those with chronic disease will further develop hepatocirrhosis and hepatocellular carcinoma respectively.
HCV is a kind of RNA virus of Flavividae family. The studies (see, e.g., Choo et al, Science 244:359-362 (1989); Choo et al, Proc. Natl. Acad. Sci. USA 88:2451-2455 (1991); Han et al, Proc. Natl. Acad. Sci. USA 88: 1711-1715 (1991)) indicated that the HCV genome is a single positive RNA strand of about 9.4 kb and has an open reading frame (ORF) that nearly spans the whole genome. The ORF encodes a viral ployprotein precursor of 3011 or 3010 amino acids. The proteins encoded by the HCV genome include the nucleocapsid core protein(C), the two envelope glycoproteins (E1 and E2), and the genome contains five regions corresponding to nonstructural proteins (NS1˜NS5). In the genome, the hypervariable region 1 (HVR1) from E2 region of Hepatitis C virus contains important antigenic epitopes that can induce neutralizing antibodies (see, e.g., Shirai et al, J. Immunol, 162:568-576(1999)). However, the gene of HVR1 may be greatly mutated due to immunological selection so that HCV can escape from the recognition of the body immune system. This might be the major cause whereby HCV results in chronic hepatitis.
At present, the mechanism whereby HCV causes disease is not well understood, and there are no very clinically effective therapeutic methods and vaccines to prevent its propagation. Interferon (IFN) is often used in the current clinical therapy to degrade viral RNA by activating RNase L, but the long-term effective rate of the therapy is only about 20%. Manns et al (The Lancet, 358: 958-965 (2001)) treated Hepatitis C by using both of pegylated interferon and ribavirin. While this therapy is particularly effective in the case of patients infected by viral strains belonging to genotypes 2 and 3, it only has a limited effect on genotypes 1a, 1b and 4. Therefore, people have tried by a variety of means to research and develop vaccines that decrease HCV infection and medicines that cure hepatitis.
From the study of the HCV genome, people have found a number of immunogenic peptides against HCV, which can induce an immune response to HCV in the body. For example, U.S. Pat. No. 5,709,995A of Chisari et al discloses a group of peptides that stimulate HCV-specific cytotoxic T lymphocyte (CTL). WO2003/097677A discloses HCV antigenic peptides and compositions thereof, which have the ability to induce strong immune responses. CN1194986C and CN1216075C of the inventor of the present invention also disclose a group of HCV immunogenic peptides that can induce the generation of antibodies. Although it was thought in the early time that HCV caused liver damage by virus-induced cytopathy like certain viruses (e.g., Hepatitis C virus, EB virus), the recent studies indicated that the immune response against HCV is the major cause leading to liver damage. Particularly in chronic patients with HCV, the lymphocyte (especially cytotoxic T lymphocyte) can not completely effectively eliminate HCV, but in the process of eliminating hepatocytes infected with HCV, it results in immunological hepatocyte damage, and thus leads to hepatocyte apoptosis and even to hepatocirrhosis and hepatocellular carcinoma (see, for example, Nelson et al, J. Immunol., 158:1473-1481(1997); Wong et al, J. Immunol., 160:1479-1488 (1998); Ruggieri et al, Virology, 229: 68-76 (1997)). Therefore, the HCV immunogenic peptide used as vaccine will induce an immune response against HCV that might lead to immunological liver damage. Practically, such mechanism greatly impedes the development of prophylactic vaccine or therapeutical medicine for Hepatitis C (especially chronic Hepatitis C) from such HCV immunogenic peptides.
Except immunological liver damage and pathogenic liver damage, it is well known that hepatotoxic chemical substance can also induce liver damage. It is known that some drugs can cause liver damage, and result in hepatic cytolysis and necrosis. For example, the analgetic acetaminophen (i.e., Panadol, the chemical name of which is 4-(N-acetylamino)phenol), when administrated in a large dose, is a kind of liver-damaging substance that can induce necrosis of human liver. For example, long-term administration of antibiotic, such as rifampicin, pyrazinamide, and isoniazide, and long-term administration of estrogen and the like in the period of menopause, also can cause severe hepatocyte necrosis, leading to liver damage, such as acute or chronic hepatitis, jaundice, and hepatic fibrosis and the like. The liver-damaging substances include substance that can generate many active free radicals, particularly include substance that can generate oxygen-derived free radicals, which induce hepatotoxity via oxidation.
After massive research, the inventor obtained an HCV immunogenic peptide and derivative thereof that can prevent or treat liver damage, and surprisingly, the said liver damage is not limited to immunological damage of hepatocyte infected with HCV. For example, the peptide and derivative thereof of the invention can be used to prevent or treat immunological liver damage, pathogenic liver damage and hepatotoxic chemical substance-induced liver damage.